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Mortality Attributable to tobacco –         A Global Report          E Tursan d’Espaignet          Tobacco Free Initiative...
WHO Global Report: Mortality Attributable             to Tobacco Estimates for high, low and middle income  countries. E...
Contents of the Report Builds on global estimates  for 2004 provided in WHO  Report “Global Health  Risks: Mortality and ...
The global burden of tobacco use Tobacco is the only legal drug that kills many of its users  when used exactly as intend...
The global burden of tobacco use Use of tobacco among adults in developing  countries is increasing. Accelerating rates ...
Global Voluntary NCD Targets for 2025under consideration by Member States Relative reduction in current tobacco smoking b...
Surveillance of tobacco Art. 20 of the WHO FCTC requires parties to adopt  standard methods of data collection to measure...
Method of calculating mortality         attributable to tobacco The Population Attributable Fraction (PAF) method is  the...
The Smoking Impact Ratio (SIR) method To estimate the excess mortality from lung cancer in  smokers in a country’s popula...
Causes of death are categorised into  3 broad groups Group 1: Communicable diseases:  - Tuberculosis  - Lower respiratory...
Report Layout
Report Layout
Major Findings In 2004, about 5 million adults aged 30 years and  over died from direct tobacco use (smoking and  smokele...
Findings           Source: WHO Global Report: Mortality Attributable to Tobacco, 2012http://www.who.int/tobacco/publicatio...
Communicable disease findings 5% of all deaths from communicable diseases: 7% of all deaths due to tuberculosis 12% of ...
NCD Findings NCDs account for 14% of all deaths are attributed to tobacco. Cardiovascular diseases: 10%  Of those adults...
Thank you for your attention
Stages of the Cigarette Epidemic on Entering Its Second Century            Michael Thun            Richard Peto           ...
Full article in 20th Anniversary Edition           of Tobacco Control           2012;21:96-101
Original WHO Model    Four Stages of the Cigarette EpidemicSource: Lopez et al. Tobacco Control 1994
Value of this Model• Portrays epidemic as a continuum rather than as a  series of isolated events.• Allows each country to...
Disadvantages of original model• Based on the experience in  economically developed countries• No corresponding model coul...
Methods• Assess trends in smoking-attributed mortality  by sex in 41 developed countries from 1950-  ”present” using Peto-...
Results1. The original model still provides a   reasonably useful description of the   epidemic in many developed   countr...
Male and female smoking prevalence have converged at younger ages inmost high resource countries (& have crossed over at a...
Trends in smoking-attributed deaths infour high resource countries, 1950-2005                                             ...
However, the staging system in original     model does not fit China or IndiaSource: Lopez et al. Tobacco Control 1994
Solution• Allow the stage of the epidemic to differ in  men and women.• Designate these stages based on sex-  specific data
Evolution of the Smoking Epidemic                   in Men% of smokers among adults                                       ...
Evolution of the Smoking Epidemic                 in Women                                                                ...
Conclusions1. Predictions from the model fit well qualitatively   with recent trends in high resource countries.2. Also re...
Thank You
Updated data on smoking-related deaths in 41 countries available at:• http://tobaccocontrol.bmj.com/content/21/2.toc• http...
The global burden of deaths from tobacco is           shifting from developed to developing                          count...
Smoking-attributed mortality estimates in original model based on U.S. data
US data updated to most recent year available:Prevalence through 2010, Smoking-Attributed Mortalitythrough 2005 % of smoke...
Trends in Cigarette Smoking Prevalence (%),  by Sex, Adults 18 and Older, US, 1965-2010                        60         ...
Prevalence of smoking - UK                                  Men                                                  Women    ...
Australia                                  Men                                                  Women              70     ...
Epidemic lags in women in all Southernand most Eastern European countries                                                 ...
Trends in lung cancer death ratesamong men in U.S., U.K. and Commonwealth                          United Kingdom         ...
Lung cancer mortality age 35-69,       for selected countries, 1960-2000            UK                           US       ...
Trends in lung cancer death rates amongmen in Southern Europe                             Italy                           ...
Source: Li et al. (2011) NEJM Vol. 364:25
Active Smoking, Secondhand Smoke       and Breast Cancer Risk                     Kenneth C. Johnson, PhD                 ...
Overview Passive smoking meta-analyses 3 Interpretations 2004, 2005, 2006 Canadian Expert Panel 2009 Active smoking ri...
 Passivesmoking Secondhand smoke Involuntary smoking Environmental tobacco smoke (ETS)
Expert Panel Approach  Based on the weight of evidence from:        - epidemiologic studies,        - toxicological studie...
20 Mammary Carcinogens in SHS         Acrylamide         Acrylonitrile        1,3-Butadiene           Isoprene        Nitr...
Undiluted Sidestream TobaccoSmoke versus Mainstream Smoke Examples             Ratio in Sidestream to                     ...
Meta-analysis of Studies of PassiveSmoking and Breast Cancer • 20 Studies published by end of 2004 • 8 cohort studies, 12 ...
0.1                                                                                                                       ...
Thank god! A panel of experts
Thank god! A panel of expertsThank god! A panel of experts
Conclusions – Cal EPA Report (2005) Passive Smoking & Breast Cancer “Overall, the weight of evidence  (including toxicolo...
Thank god! A panel of experts                          Thank god! A panel of expertsThank god! A panel of experts
Surgeon General’s Conclusion“ The evidence is suggestive but notsufficient to infer a causal relationshipbetween secondhan...
California EPA and Surgeon General    found similar passive risk estimates                   California EPA Report    Surg...
A Question of Interpretation:              Balancing ConcernsResults from Cohort Studies versus Case-control Studies?Expos...
Reference: Rothman & Greenland. Modern Epidemiology 2nd Ed.
Studies of Excess Lung Cancer Risk for     Non-Smokers From Second-Hand Smoke             250                             ...
SHS and Breast Cancer Studies since 2006    Lissowska et al. (2007, 2007b) lifetime SHS assessment    women under age 45...
SHS and Breast Cancer Studies Since 2009   Ahern et al. (2009) lifetime assessment,   No consistent risk increases found...
Secondhand Smoke and Breast      Cancer Risk – New Cohort Studies        SHS Exposure                California           ...
Surgeon General’s Basic Premise“There is substantial evidence that active smoking is not associated with an increased risk...
Surgeon General Relies Heavily on     53 Study Collaborative Reanalysis“In a pooled analysis of data from 53 studies, the ...
Overall risk for premenopausal breast cancer and smoking – greater      than overall alcohol risk?Active smoking (non-drin...
Increased Breast Cancer Risk with Active             Smoking in Recent Cohort Studies                                     ...
Smoking Pack-years, NAT2 Acetylators Status,               Menopausal Status and Breast Cancer Risk                       ...
Smoking Pack-years, NAT2 Acetylators Status,               Menopausal Status and Breast Cancer Risk                       ...
Cohort Studies of Active Smoking and Breast Cancer Risk      (>500 cases) by Highest Exposure Categories                  ...
Cohort Studies of Active Smoking and Breast Cancer Risk            by Highest Exposure Categories                     Youn...
Cohort Studies of Active Smoking and Breast Cancer Risk            by Highest Exposure Categories                         ...
Cohort Studies of Active Smoking and Breast Cancer Risk             by Highest Exposure Categories                     You...
Table 13: Cohort Studies – Age of Smoking            Initiation And Breast Cancer Risk                           Earliest ...
US Radiologic Technologists Cohort:        Smoking Before 1st BirthReference: M. Ha, K. Mabuchi, A. J. Sigurdson, D. M. Fr...
US Radiologic Technologists Cohort:        Smoking After 1st BirthReference: M. Ha, K. Mabuchi, A. J. Sigurdson, D. M. Fre...
US Radiologic Technologists Cohort:Smoking Risk Before and After 1st BirthReference: M. Ha, K. Mabuchi, A. J. Sigurdson, D...
Source: Xue et al. Cigarette smoking and the incidence of breast cancer. Arch Intern Med 2011; 171(2):125-133.
Harvard Nurses Health Study Cohort  Smoking before First Birth and   Increased Breast Cancer Risk
Lung Cancer and Passive Smoking
14 Studies of Passive Smoking and Lung Cancer:      Causal connection established 1986                                    ...
Cumulative Meta-analysis of Spousal ETSExposure and Lung Cancer Risk 1981-1999
Secondhand Smoke ConclusionBased on the weight of evidence presented by:   - the California EPA   - the Surgeon General, a...
Active Smoking ConclusionBased on the weight of evidence from:   - epidemiologic studies,   - toxicological studies and   ...
Lung disease in relation to    tobacco exposure Ioana Munteanu , Fl. Mihaltan  “Marius Nasta” Institute ofpneumology Bucha...
• Effects of cigarette smoke on the lung• History• Lung diseases
• Effects of cigarette smoke on the lung• History• Lung disease
Europe - 650,000 deaths / year are attribute to smoking
THE MECHANISM OF INDUCED LUNG INJURY                                                    850-900                           ...
Pulmonary disease in relation to               smoking• Diseases in which smoking is directly involved and  has negative e...
Risk of developing a disease caused by                smoking• As compared to nonsmokers, smoking is  estimated to increas...
Pulmonary disease in relation to                  smoking• Diseases whose evolution is worsened by smoking•   Chronic infl...
• Effects of cigarette smoke on the lung• History• Lung disease
History                           In 1950 , Prof . R. Doll began his studies on the role                           of smok...
1981: Earliest evidence of the passive smoking involvement in lung cancerdevelopment Takeshi Hirayama (Japan)             ...
• Effects of cigarette smoke on the lung• History• Lung diseases
• COPD
PATHOGENESIS AND PATHOPHYSIOLOGY OF LUNG LESIONS INDUCED                             BY TOBACCOCigarette smoke            ...
Lifetime risk of developing chronic obstructive                   pulmonary disease                                 Dr And...
Smoking Cessation: Improvement in                                     Postbronchodilator FEV1 Decline     Susceptible smok...
COPDThe exact role of smoking cessation on airway inflammation inpatients with COPD remains unknownStudies- Inflammation...
Predictors of Mortality in Patients with Stable            COPD Esteban, 2008,Five-year prospective cohort study. 600 stab...
• Asthma
Asthma    smoking is a risk candidate for development of asthma smoking is more prevalent in individuals with asthma than ...
Effects of smoking cessation on airflow obstruction and quality        of life in asthmatic smokers. Jang AS,Korea 2010   ...
Lung cancer
The lung cancer risks of smoking vary with the         quantitative aspects of smoking• Duration of smoking is the stronge...
THE LUNG CANCER RISK INCREASEs EXPONENTIALLY WITH THE NUMBER OF YEARS        AND THE NUMBER OF CIGARETTE SMOKED BY DAY    ...
Lung Cancer in Patients with Chronic Obstructive Pulmonary Disease                     Incidence and Predicting Factors   ...
Tobacco-attributable cancer burden in     the UK in 2010, DM Parkin
Pack-Years of Cigarette Smoking as a Prognostic Factorin Patients With Stage IIIB/IV Nonsmall Cell Lung CancerJanjigian, C...
Infectious diseases - tuberculosis
The association between smoking and tuberculosis has         been investigated since 1918                  Int J Tuberc Lu...
The reduction of tuberculosis risks by         smoking cessation            Wen, et al.--2010
Smoking and mortality from tuberculosis andother diseases in India: retrospective study of43 000 adult male deaths and 35 ...
Tobacco smoking and pulmonary         tuberculosis      Kolappan, Gopi--2002
Thank you
Genetic and Lifestyle Modifiers of                 Cancer   Smoking on Disease Risk                  Woon-Puay Koh        ...
List of cancers associated with           cigarette smoking………   Lung   Mouth and pharynx   Larynx   Esophagus   Stom...
Do all smokers get cancer?
What modifies a smoker’s risk of cancer?   Risk of lung cancer in smokers       Body mass index   Risk of colorectal ca...
Singapore Chinese Health StudyEligibility criteria:   Singapore Chinese, housing estate residents, ages                   ...
Cigarette smoking   31% ever smokers among the 61,321 subjects               Men (n=27,292)          Women (n=34,028)    ...
Cigarettes and Lung Cancer Risk  1,042 incident lung cancer cases in this cohort       after a mean follow-up of 10.7 year...
Body Mass Index in Relation to Lung   Cancer Risk by Smoking Status                    Never               Former         ...
Smoking and lung cancer risk by levels of BMI           <20 kg/m2        20-<24 kg/m2     24-<28 kg/m2      >=28 kg/m2Smok...
Smoking and lung cancer risk by levels of BMI            <20 kg/m2       20-<24 kg/m2       24-<28 kg/m2         >=28 kg/m...
Biological plausibility   Body mass index influences a smoker’s risk    of lung cancer   Lean smokers have increased oxi...
Public Health Implication   Rapid increase in smoking prevalence in    developing countries such as China and India    in...
Smoking and Colorectal Cancer Risk
“Lifestyle” cancer     Obesity     Western diet     Physical inactivity     Smoking
Current smoking and colorectal cancerrisk: Meta-analysis (18 cohort studies)         Tsoi KK et al Clin Gastroenterol Hepa...
Colonic carcinogens in cigarette   Polycyclic aromatic hydrocarbons (PAHs) and    heterocyclic aromatic amines (HAAs)   ...
GST enzymes   5 main classes: alpha (GSTA), mu (GSTM), pi    (GSTP), theta (GSTT) and zeta (GSTZ)   GSTM1, GSTT1 and GST...
GSTM1 and GSTT1 polymorphisms   The homozygous deletion genotypes of GSTM1    and GSTT1 result in an absence of GSTM1 and...
GSTP1 polymorphism   A transition of adenine (A) to    guanine (G) at nucleotide 313 in    exon 5 of the GSTP1 gene resul...
GST/Smoking/Colorectal Cancer           GSTs can deactivate HAAs and PAHs Hence, individuals with genetically   determined...
Nested case-control study within the  Singapore Chinese Health Study   480 incident colorectal cancer cases within    the...
Cigarettes and Colorectal Cancer                Colorectal         Colon              RectalSmoking level   OR (95% CI)*  ...
GSTs and Colorectal Cancer                  Colorectal         Colon              RectalGSTM1             OR (95% CI)*    ...
GSTs and Colorectal Cancer  No. of “null  Colorectal       Colon               Rectal  or low        OR (95% CI)*     OR (...
GSTs, Cigarettes and Colorectal CancerWith zero GST “null or low activity” genotype (22.5%)                   Colorectal  ...
GSTs, Cigarettes and Colorectal Cancer With one GST “null or low activity” genotype (41.4%)                  Colorectal   ...
GSTs, Cigarettes and Colorectal CancerWith two or three GST “null or low activity” genotypes (36.1%)                  Colo...
Biological Plausibility   The GSTM1/GSTT1/GSTP1 genotypic profile of    a cigarette smoker affects his/her risk of    dev...
Gene-Environment-Smoking Interaction   Wide variation in cancer incidence among smokers   A range of genetic and lifesty...
Gene-Environment-Smoking Interaction   Understand the mechanistic pathway of    tobacco-linked carcinogenesis   Identify...
Acknowledgement     Cohort Study Team              Professor Mimi Yu     Singapore Cancer Registry      Assoc Prof Yua...
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  1. 1. Mortality Attributable to tobacco – A Global Report E Tursan d’Espaignet Tobacco Free Initiative WHO Geneva tursandespaignet@who.int
  2. 2. WHO Global Report: Mortality Attributable to Tobacco Estimates for high, low and middle income countries. Effects of direct use of smoking (and smokeless) tobacco among adults aged 30+ for communicable and non-communicable diseases.
  3. 3. Contents of the Report Builds on global estimates for 2004 provided in WHO Report “Global Health Risks: Mortality and burden of disease attributable to selected major risks” , 2009. Expansion to provide data at WHO Regional and country levels
  4. 4. The global burden of tobacco use Tobacco is the only legal drug that kills many of its users when used exactly as intended by manufacturers. Tobacco kills: – Direct tobacco smoking: 5 million people / year – Second hand smoke: 600,000 people / year – More than tuberculosis, HIV/AIDS and malaria combined If effective measures are not urgently taken, tobacco could, in the 21st century, kill over 1 billion people: 999,999,999 + 1
  5. 5. The global burden of tobacco use Use of tobacco among adults in developing countries is increasing. Accelerating rates of tobacco among women. Significant social and economic handicap for families, communities and governments. Contributes to family poverty.
  6. 6. Global Voluntary NCD Targets for 2025under consideration by Member States Relative reduction in current tobacco smoking by 40% by 2025 Relative reduction in age-standardised death rate from non-communicable diseases by 25% (using 2010 as baseline)
  7. 7. Surveillance of tobacco Art. 20 of the WHO FCTC requires parties to adopt standard methods of data collection to measure magnitude, patterns, determinants and consequences of tobacco use and exposure. Much of WHO activities until now has been on measuring the magnitude of the problem through youth and adult surveys. WHO is now also monitoring outcomes: - Mortality report - Pregnancy report (mid-late 2012)
  8. 8. Method of calculating mortality attributable to tobacco The Population Attributable Fraction (PAF) method is the proportion of deaths that may be attributed to exposure to tobacco (or any other risk factor). The PAF formula is made up of two factors: – The prevalence (P) of tobacco use in the population; – The relative risk (RR) of developing a disease among those who smoke or consume smokeless tobacco, compared with those who do not use tobacco.
  9. 9. The Smoking Impact Ratio (SIR) method To estimate the excess mortality from lung cancer in smokers in a country’s population relative to the excess mortality in smokers in the reference population: - CLC and NLC are lung cancer rates in the population and in • never smokers in a country’s population - S*LC and N*LC are lung cancer rates in smokers and never smokers of the reference population. The resulting SIR estimate is then used instead of P in the PAF formula:
  10. 10. Causes of death are categorised into 3 broad groups Group 1: Communicable diseases: - Tuberculosis - Lower respiratory tract infection Group 2: Non-communicable diseases - Cancers : Lung cancer - Cardiovascular diseases: Heart disease, Stroke - Respiratory diseases – Chronic Obstructive Pulmonary Disease Does not include: Group 3: Injuries (external causes)
  11. 11. Report Layout
  12. 12. Report Layout
  13. 13. Major Findings In 2004, about 5 million adults aged 30 years and over died from direct tobacco use (smoking and smokeless) around the globe: 1 DEATH EVERY 6 SECONDS! 12% of all 30+ deaths attributed to tobacco. Mortality higher among men than among women
  14. 14. Findings Source: WHO Global Report: Mortality Attributable to Tobacco, 2012http://www.who.int/tobacco/publications/surveillance/rep_mortality_attributable_tobacco/en/i ndex.html
  15. 15. Communicable disease findings 5% of all deaths from communicable diseases: 7% of all deaths due to tuberculosis 12% of deaths due to lower respiratory infections
  16. 16. NCD Findings NCDs account for 14% of all deaths are attributed to tobacco. Cardiovascular diseases: 10% Of those adults aged 30-44 years who died from ischemic heart disease, 38% of the deaths were attributable to tobacco. Cancer deaths: 22% 71% of all lung cancer deaths are attributable to tobacco use. Respiratory diseases: 36% 42% of all chronic obstructive pulmonary disease are attributable to tobacco use.
  17. 17. Thank you for your attention
  18. 18. Stages of the Cigarette Epidemic on Entering Its Second Century Michael Thun Richard Peto Jillian Boreham Alan Lopez WCTOH Singapore March, 2012
  19. 19. Full article in 20th Anniversary Edition of Tobacco Control 2012;21:96-101
  20. 20. Original WHO Model Four Stages of the Cigarette EpidemicSource: Lopez et al. Tobacco Control 1994
  21. 21. Value of this Model• Portrays epidemic as a continuum rather than as a series of isolated events.• Allows each country to find itself on this continuum• Communicates the long delay between the uptake of widespread smoking and the full eventual consequences for mortality• Indicates the paradoxical period in which prevalence falls but mortality continues to increase• Shows that without effective tobacco control, the problem will get much worse.
  22. 22. Disadvantages of original model• Based on the experience in economically developed countries• No corresponding model could be proposed for developing countries• The staging criteria based on the comparative levels of smoking & mortality in men and women.• Clearly not applicable in China or India.
  23. 23. Methods• Assess trends in smoking-attributed mortality by sex in 41 developed countries from 1950- ”present” using Peto-Lopez indirect method.• Emphasize ages 35-69• Review data on smoking prevalence in GATS & GYTS• Assess applicability of the model in countries at various levels of economic development• Project the trends in prevalence & smoking- attributed mortality forward through 2025.
  24. 24. Results1. The original model still provides a reasonably useful description of the epidemic in many developed countries. • Prevalence has decreased in both sexes, although more slowly than predicted • Smoking-attributed deaths are decreasing in men but increasing or have reached a plateau in women.
  25. 25. Male and female smoking prevalence have converged at younger ages inmost high resource countries (& have crossed over at all ages in Sweden).
  26. 26. Trends in smoking-attributed deaths infour high resource countries, 1950-2005 Australia Netherlands 50 50 45 45 40 40 35 35 30 30 Percent Percent Male Male 25 25 Female Female 20 20 15 15 10 10 5 5 0 0 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 UK US 50 50 45 45 40 40 35 35 30 30 PercentPercent Male Male 25 25 Female Female 20 20 15 15 10 10 5 5 0 0 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 Percent indicates percentage of all deaths attributed to smoking in age range 35-69.
  27. 27. However, the staging system in original model does not fit China or IndiaSource: Lopez et al. Tobacco Control 1994
  28. 28. Solution• Allow the stage of the epidemic to differ in men and women.• Designate these stages based on sex- specific data
  29. 29. Evolution of the Smoking Epidemic in Men% of smokers among adults % of deaths caused by smoking STAGE 1 STAGE 2 STAGE 3 STAGE 4 70 40 35 60 % male smokers 30 50 % male deaths 25 40 20 30 15 20 10 10 5 0 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Sub-Saharan Africa China, Norway Western Europe, USA, UK, Australia Southeast Asia Greece, Latin American
  30. 30. Evolution of the Smoking Epidemic in Women % of deaths caused by% of smokers among adults smoking STAGE 1 STAGE 2 STAGE 3 STAGE 4 70 40 35 60 30 50 25 40 20 30 15 % female smokers 20 % female deaths 10 10 5 0 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Sub-Saharan Africa Eastern and Southern Western Europe, USA, UK, Europe Australia Southeast Asia, China
  31. 31. Conclusions1. Predictions from the model fit well qualitatively with recent trends in high resource countries.2. Also reasonably compatible with trends among men in developing countries3. The stages as defined by the original model are not applicable to China or India4. Modifying the model to allow different stages for men and women will improve its generalizability to developing countries.
  32. 32. Thank You
  33. 33. Updated data on smoking-related deaths in 41 countries available at:• http://tobaccocontrol.bmj.com/content/21/2.toc• http://www.ctsu.ox.ac.uk/~tobacco/
  34. 34. The global burden of deaths from tobacco is shifting from developed to developing countries Tobacco deaths 2000 Tobacco deaths 2030 Developed 2 million 3 million Developing 2 million 7 million By 2030, 7 of every 10 tobacco attributable deaths projected to be in developing countriesWorld Health Organization. 1999. Making a Difference. World Health Report. 1999.Geneva, Switzerland
  35. 35. Smoking-attributed mortality estimates in original model based on U.S. data
  36. 36. US data updated to most recent year available:Prevalence through 2010, Smoking-Attributed Mortalitythrough 2005 % of smokers among adults % of deaths caused by STAGE 2 STAGE 3 STAGE 4 smoking STAGE 1 70 40 35 60 % male smokers 30 50 % male deaths 25 40 % female smokers 20 30 15 20 % female deaths 10 10 5 0 0 0 10 20 30 40 50 60 70 80 90 100 1900 1920 1940 1960 1980 2000
  37. 37. Trends in Cigarette Smoking Prevalence (%), by Sex, Adults 18 and Older, US, 1965-2010 60 (52%) 50 Prevalence (%) 40 30 Men (21.5%) (34%) 20 Women (17.3%) 10 0 1965 1974 1979 1983 1985 1990 1992 1994 1995 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 YearSource: National Health Interview Survey, 1965-2010, National Center for Health Statistics, Centers for DiseaseControl and Prevention, 2011.
  38. 38. Prevalence of smoking - UK Men Women 70 60 60 50 50 40 Prevalence 40 30 30 20 20 10 10 0 0 46- 51- 56- 61- 66- 71- 76- 81- 86- 91- 96- 01- 46- 51- 56- 61- 66- 71- 76- 81- 86- 91- 96- 01- 50 55 60 65 70 75 80 85 90 95 00 05 50 55 60 65 70 75 80 85 90 95 00 05 Year YearSource: IMASS v4, 2010
  39. 39. Australia Men Women 70 70 60 60 50 50 Prevalence 40 40 30 30 20 20 10 10 0 0 46- 51- 56- 61- 66- 71- 76- 81- 86- 91- 96- 01- 46- 51- 56- 61- 66- 71- 76- 81- 86- 91- 96- 01- 50 55 60 65 70 75 80 85 90 95 00 05 50 55 60 65 70 75 80 85 90 95 00 05 Year YearSource: IMASS v4, 2010
  40. 40. Epidemic lags in women in all Southernand most Eastern European countries Greece Poland 50 45 45 40 40 35 35 30 30 Percent Percent Male 25 Male 25 Female 20 Female 20 15 15 10 10 5 5 0 0 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 Russia Romania 50 50 45 45 40 40 35 35 30 30 PercentPercent Male Male 25 25 Female Female 20 20 15 15 10 10 5 5 0 0 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005
  41. 41. Trends in lung cancer death ratesamong men in U.S., U.K. and Commonwealth United Kingdom United States Canada New Zealand Australia
  42. 42. Lung cancer mortality age 35-69, for selected countries, 1960-2000 UK US France HungaryPeto R, Lopez AD et al. http://www.ctsu.ox.ac.uk/~tobacco/index.htm
  43. 43. Trends in lung cancer death rates amongmen in Southern Europe Italy Greece Spain
  44. 44. Source: Li et al. (2011) NEJM Vol. 364:25
  45. 45. Active Smoking, Secondhand Smoke and Breast Cancer Risk Kenneth C. Johnson, PhD Department of Epidemiology and Community Medicine Faculty of Medicine University of Ottawa March 23, 2012 World Conference on Tobacco or Health Singapore
  46. 46. Overview Passive smoking meta-analyses 3 Interpretations 2004, 2005, 2006 Canadian Expert Panel 2009 Active smoking risk Conclusions
  47. 47.  Passivesmoking Secondhand smoke Involuntary smoking Environmental tobacco smoke (ETS)
  48. 48. Expert Panel Approach Based on the weight of evidence from: - epidemiologic studies, - toxicological studies and - understanding of biological mechanisms What can be concluded about the relationships between: - passive smoking and breast cancer - active smoking and breast cancer
  49. 49. 20 Mammary Carcinogens in SHS Acrylamide Acrylonitrile 1,3-Butadiene Isoprene Nitromethane Propylene Oxide Dibenz[a,h]anthracene Vinyl chloride 4-Aminobiphenyl Urethane Benzene Nitrobenzene Benzo[a]pyrene ortho-Toluidine Dibenzo[a,e]pyrene Dibenzo[a,i]pyrene Dibenzo[a,l]pyrene N-Nitrosodiethylamine N-Nitrosodi-n-butylamine
  50. 50. Undiluted Sidestream TobaccoSmoke versus Mainstream Smoke Examples Ratio in Sidestream to Mainstream Smoke - Carbon monoxide 2.5-15 times as much - Nitrogen Oxides 3.7-12.8 times - Nicotine 1.3-21 as much - Benzene 8-10 times as much - Formaldehyde 50 times as much - NNK 1-22 times as much - Benz(a)pyrene 2.5-20 times as much - Nickel 13-30 times as much - Tar 1.1-15.7 times Source: Hoffmann and Hecht, 1989
  51. 51. Meta-analysis of Studies of PassiveSmoking and Breast Cancer • 20 Studies published by end of 2004 • 8 cohort studies, 12 case control studies • 7 in Asia, 3 in Europe, 10 in North America • 9 before 2000, 11 since 2000 • Disease endpoint (18 diagnosis, 2 death) • Significant age restrictions in 7 studies • Control for potential confounders in most studiesReference: Johnson, KC. Accumulating Evidence on Passive and Active Smoking and Breast Cancer Risk Int J Cancer, May 2005
  52. 52. 0.1 1 Hi ra 10 y ama Wa , 19 rten 92 ber g et al . , 200 Re y 0 nold s et Cohort a l. , 20 0 Ha n aok 4 a et al . , 200 San 4 dle r et a l. , 1 985 Mil l ik an et a passive smoking exposure l. , 1 998 De l f ino et a l ., 2 Scr 000 Case-control ubs Studies likely to have missed important sources of ol e et a l ., 2 Gam 004 m on et a l., 2 00 4 Sm i th et a l ., 1 Mor 994 abi a et a l ., 1 996 Zha o et al ., 199 Joh 9 nsoRelative risk (95% CI) n et al . , 200 Kro 0 pp et a l., 2 passive smoking exposure Li ss 00 2 ows ka e t al . 200 6 |_____________________| |___________________________| |______________________________________| Mis Studies unlikely to have missed important sources of sed Ex p osu Studies of Passive Smoking and re - Mis Coh sed ort Premenopausal Breast Cancer Risk Ex p Stu osu die s re - Be t Cas te r e-C Exp ont osu rol re A sse s sm e nt
  53. 53. Thank god! A panel of experts
  54. 54. Thank god! A panel of expertsThank god! A panel of experts
  55. 55. Conclusions – Cal EPA Report (2005) Passive Smoking & Breast Cancer “Overall, the weight of evidence (including toxicology of tobacco smoke constituents, epidemiological studies, and breast biology) is consistent with a causal association between ETS exposure and breast cancer in younger, primarily premenopausal women”
  56. 56. Thank god! A panel of experts Thank god! A panel of expertsThank god! A panel of experts
  57. 57. Surgeon General’s Conclusion“ The evidence is suggestive but notsufficient to infer a causal relationshipbetween secondhand smoke and breastcancer.”
  58. 58. California EPA and Surgeon General found similar passive risk estimates California EPA Report Surgeon Generals 2005 1 Report 20062Exposure n Relative Risk N Relative Risk (95% CI) (95% CI)All studies 19 1.25 (1.08-1.44) 21 1.20 (1.08-1.35)Premenopausal/ 14 1.68 (1.31-2.15) 11 1.64 (1.25-2.14) Women < 50Premenopausal 5 2.20 (1.69-2.87) 6 1.85 (1.19-2.87) with lifetime exposure assessment
  59. 59. A Question of Interpretation: Balancing ConcernsResults from Cohort Studies versus Case-control Studies?Exposure misclassification versus Recall and Response Bias?Confounding by Alcohol?Is the unexposed group different in other ways?Premenopausal risk and No Postmenopausal Risk?Passive but No Active Smoking Risk?
  60. 60. Reference: Rothman & Greenland. Modern Epidemiology 2nd Ed.
  61. 61. Studies of Excess Lung Cancer Risk for Non-Smokers From Second-Hand Smoke 250 +35-220% +50-210% 200 USA 1994 150 Europe 1998Excess Lung Sweden 1998Cancer Risk Germany 1998(Percentage) 100 +1-25% China 1999 Germany 2000 50 China 2000 Canada 2001 0 Home and Work - Work Only - Spousal Higher Exposure Higher Exposure Type and Level of Exposure
  62. 62. SHS and Breast Cancer Studies since 2006  Lissowska et al. (2007, 2007b) lifetime SHS assessment  women under age 45, total SHS 1.00, 1.36, 1.52, 2.02 (0.94-4.36)  Roddam et al. (2007) spousal exposure only (41% exposed)  risk increases not found  Lin et al. (2008) Japan Collaborative Cohort Study, age 40-79; 196 never smoker cases; 8 ever smoker cases,  no analyses with unexposed referent group  Pirie et al. (2008) SHS, age 0, 10, current spousal (age 53-67) (11% exposed) risk increases not found  Pirie et al. (2008) Meta-analysis retrospective/prospective; no subcategories
  63. 63. SHS and Breast Cancer Studies Since 2009 Ahern et al. (2009) lifetime assessment, No consistent risk increases found Reynolds et al (2010) California Teachers Cohort – Updated evaluation of SHS – Lifetime exposure assessment Luo et al (2011) – Women’s Health Initiative Cohort (U.S) - Lifetime Exposure Assessment Xue et al (2011) – Updated evaluation of the Harvard Nurses’ Health Cohort - exposure assessment limited - occupational assessment limited to current exposure in 1982
  64. 64. Secondhand Smoke and Breast Cancer Risk – New Cohort Studies SHS Exposure California Women’s Health Teachers Cohort[48] Initiative Cohort[27] Adjusted HR Adjusted HR (95% (95% CI) CI)No reported lifetime 1.00 1.00exposureAny childhood exposure 1.06 (0.94-1.19) 1.19 (0.93-1.53)Any adult home exposure 1.04 (0.92-1.16) 0.91 (0.70-1.19)Any workplace exposure 1.02 (0.93-1.13) 1.01 (0.82-1.26)Highest cumulative lifetime 1.26 (0.99-1.60) 1.32(1.04-1.67)exposure (vs. no lifetimeexposure from any source).
  65. 65. Surgeon General’s Basic Premise“There is substantial evidence that active smoking is not associated with an increased risk of breast cancer in studies that compare active smokers with persons who have never smoked.” Surgeon General’s Report 2006 (p 446)
  66. 66. Surgeon General Relies Heavily on 53 Study Collaborative Reanalysis“In a pooled analysis of data from 53 studies, the relative risk for women who were current smokers versus life-time non-smokers was 0.99 (95% CI, 0.92-1.05) for the 22,225 cases and 40,832 controls who reported not drinking alcohol. The effect of smoking did not vary by menopausal status.” Surgeon General’s Report 2006 (p 446)
  67. 67. Overall risk for premenopausal breast cancer and smoking – greater than overall alcohol risk?Active smoking (non-drinkers) Relative Risk current vs never 0.99 (0.92-1.05) ever vs never 1.03 (0.98-1.07) ever vs never premenopausal 1.07 (0.8-1.4)Alcohol Relative Risk ever vs never drinkers 1.06 Alcohol risk = 7.1% risk increase per drink/day
  68. 68. Increased Breast Cancer Risk with Active Smoking in Recent Cohort Studies ExposureStudy Measure Relative Risk (95% CI)Cancer Prevention II 40+ years 1.38 (1.05-1.83) 40+ cig/day 1.74 (1.15-2.62)Nurses Health Study 15+ cig/day 1.5 (1.1-2.0)California Teachers 31 pack-yrs 2.05 (1.20-3.49) (premeno)Canadian Breast Screening Cohort 40+ years and 1.83 (1.29-2.61) >20 cig/dayNorwegian/Swedish Cohort Study 20+ pack-yrs 1.46 (1.11-1.93) Initiation 10-14 1.48 (1.03-2.13)Japanese Public Health Center Ever active 3.9 (1.5-9.9) (premeno)References: Calle et al. 1994; Hunter et al. 1997; Reynolds et al. 2004; Terry et al. 2002; Gram et al. 2005;Hanaoka et al 2004.
  69. 69. Smoking Pack-years, NAT2 Acetylators Status, Menopausal Status and Breast Cancer Risk NAT2 Slow Acetylators NAT2 Rapid Acetylators Premenopausal Postmenopausal Premenopausal PostmenopausalType of Pack- RR (95% CI) RR (95% CI) RR (95% CI) RR (95% CI) Analysis yearsMeta- Never 1.00 1.00 1.00 1.00 Analysis active <20 1.21 (1.00-1.45) 1.28 (1.08-1.50) 1.00 (0.80-1.24) 1.12 (0.93-1.36) >20 1.47 (1.08-2.01) 1.41 (1.15-1.72) 1.34 (0.94-1.89) 0.98 (0.77-1.26) Source: Ambrosone et al. 2008
  70. 70. Smoking Pack-years, NAT2 Acetylators Status, Menopausal Status and Breast Cancer Risk NAT2 Slow Acetylators NAT2 Rapid Acetylators Premenopausal Postmenopausal Premenopausal PostmenopausalType of Pack- RR (95% CI) RR (95% CI) RR (95% CI) RR (95% CI) Analysis yearsMeta- Never 1.00 1.00 1.00 1.00 Analysis active <20 1.21 (1.00-1.45) 1.28 (1.08-1.50) 1.00 (0.80-1.24) 1.12 (0.93-1.36) >20 1.47 (1.08-2.01) 1.41 (1.15-1.72) 1.34 (0.94-1.89) 0.98 (0.77-1.26)Pooled Never 1.00 1.00 1.00 1.00 Analysis active <20 1.05 (0.86-1.28) 1.23 (1.03-1.46) 0.91 (0.72-1.16) 1.10 (0.89-1.35) >20 1.49 (1.08-2.04) 1.42 (1.16-1.74) 1.29 (0.89-1.86) 0.88 (0.69-1.13) Source: Ambrosone et al. 2008
  71. 71. Cohort Studies of Active Smoking and Breast Cancer Risk (>500 cases) by Highest Exposure Categories Youngest age ofFirst author, year initiationCalle (1994) 1.59 (1.17-2.15)Egan (2002) 1.19 (1.03-1.37)Al-Delaimy(2004) 1.29 (0.97-1.71) 8 of 8 positive;Reynolds (2004) 1.17 (1.05-1.30) 4 of 8 Stat SigLawlor (2004)Gram (2005) 1.48 (1.03-2.13)Olson (2005) 1.12 (0.92-1.36)Cui (2006) 1.11 (0.97-1.28)Ha (2007) 1.48 (0.77-2.84) Source: Canadian Expert Panel on Tobacco Smoke and Breast Cancer Risk, 2009
  72. 72. Cohort Studies of Active Smoking and Breast Cancer Risk by Highest Exposure Categories Youngest age of Longest durationFirst author, year initiation before pregnancyCalle (1994) 1.59 (1.17-2.15)Egan (2002) 1.19 (1.03-1.37) 1.13 (0.99-1.31)Al-Delaimy(2004) 1.29 (0.97-1.71) 1.10 (0.80-1.52)Reynolds (2004) 1.17 (1.05-1.30) 1.13 (1.00-1.25) 9 of 9 positive; 1.06 (0.72-1.56) 4 of 9 Stat SigLawlor (2004) 1.04 (0.67, 1.59)Gram (2005) 1.48 (1.03-2.13) 1.27 (1.07-1.37)Olson (2005) 1.12 (0.92-1.36) 1.21 (1.01-1.25)Cui (2006) 1.11 (0.97-1.28) 1.13 (1.01-1.25)Ha (2007) 1.48 (0.77-2.84) 1.78 (1.27-2.49)11 Source: Canadian Expert Panel on Tobacco Smoke and Breast Cancer Risk, 2009
  73. 73. Cohort Studies of Active Smoking and Breast Cancer Risk by Highest Exposure Categories 6 of 6 positive; Youngest age of Longest duration LongestFirst author, year 3 of 6 Stat Sig initiation before pregnancy durationCalle (1994) 1.59 (1.17-2.15)Egan (2002) 1.19 (1.03-1.37) 1.13 (0.99-1.31) 1.05 (0.90-1.21)Al-Delaimy(2004) 1.29 (0.97-1.71) 1.10 (0.80-1.52) 1.21 (1.01-1.45)Reynolds (2004) 1.17 (1.05-1.30) 1.13 (1.00-1.25) 1.15 (1.00-1.33) 1.06 (0.72-1.56)Lawlor (2004) 1.04 (0.67, 1.59)Gram (2005) 1.48 (1.03-2.13) 1.27 (1.07-1.37) 1.36 (1.06-1.74)Olson (2005) 1.12 (0.92-1.36) 1.21 (1.01-1.25) 1.18 (1.00-1.38)Cui (2006) 1.11 (0.97-1.28) 1.13 (1.01-1.25) 1.50 (1.19-1.89)Ha (2007) 1.48 (0.77-2.84) 1.78 (1.27-2.49)11 Source: Canadian Expert Panel on Tobacco Smoke and Breast Cancer Risk, 2009
  74. 74. Cohort Studies of Active Smoking and Breast Cancer Risk by Highest Exposure Categories Youngest age of Longest duration Longest Highest pack-First author, year initiation Before pregnancy duration yearsCalle (1994) 1.59 (1.17-2.15) 1.38 (1.05-1.83)Egan (2002) 1.19 (1.03-1.37) 1.13 (0.99-1.31) 1.05 (0.90-1.21)Al-Delaimy(2004) 1.29 (0.97-1.71) 1.10 (0.80-1.52) 1.21 (1.01-1.45)Reynolds (2004) 1.17 (1.05-1.30) 1.13 (1.00-1.25) 1.15 (1.00-1.33) 1.25 (1.06-1.47) 1.06 (0.72-1.56)Lawlor (2004) 1.04 (0.67, 1.59)Gram (2005) 1.48 (1.03-2.13) 1.27 (1.07-1.37) 1.36 (1.06-1.74) 1.46 (1.11-1.93)Olson (2005) 1.12 (0.92-1.36) 1.21 (1.01-1.25) 1.18 (1.00-1.38) 1.15 (0.96-1.37)Cui (2006) 1.11 (0.97-1.28) 1.13 (1.01-1.25) 1.50 (1.19-1.89) 1.17 (1.02-1.34)Ha (2007) 1.48 (0.77-2.84) 1.78 (1.27-2.49)11 5 of 5 positive, 4 of 5 statistically sigSource: Canadian Expert Panel on Tobacco Smoke and Breast Cancer Risk, 2009
  75. 75. Table 13: Cohort Studies – Age of Smoking Initiation And Breast Cancer Risk Earliest Age Smoking Relative RiskFirst Author, Year Began Category Cutoff (95% CI)Reynolds et al. (2004) <20 1.17 (1.05-1.30)Olson et al. (2005) <19 1.12 (0.92-1.36)Xue et al (2011) <18 1.04 (0.99-1.11)Cui et al. (2006) <16 1.11 (0.97-1.28)Al-Delaimy et al. (2004) <15 1.29 (0.97-1.71)Gram et al. (2005) <15 1.48 (1.03-2.13)Ha et al. (2007) <15 1.48 (0.77-2.84)
  76. 76. US Radiologic Technologists Cohort: Smoking Before 1st BirthReference: M. Ha, K. Mabuchi, A. J. Sigurdson, D. M. Freedman, M. S. Linet, M. M. Doody and M. Hauptmann, Smoking cigarettes before first childbirth and risk of breast cancer. Am J Epidemiol 166, 55-61 (2007).
  77. 77. US Radiologic Technologists Cohort: Smoking After 1st BirthReference: M. Ha, K. Mabuchi, A. J. Sigurdson, D. M. Freedman, M. S. Linet, M. M. Doody and M. Hauptmann, Smoking cigarettes before first childbirth and risk of breast cancer. Am J Epidemiol 166, 55-61 (2007).
  78. 78. US Radiologic Technologists Cohort:Smoking Risk Before and After 1st BirthReference: M. Ha, K. Mabuchi, A. J. Sigurdson, D. M. Freedman, M. S. Linet, M. M. Doody and M. Hauptmann, Smoking cigarettes before first childbirth and risk of breast cancer. Am J Epidemiol 166, 55-61 (2007).
  79. 79. Source: Xue et al. Cigarette smoking and the incidence of breast cancer. Arch Intern Med 2011; 171(2):125-133.
  80. 80. Harvard Nurses Health Study Cohort Smoking before First Birth and Increased Breast Cancer Risk
  81. 81. Lung Cancer and Passive Smoking
  82. 82. 14 Studies of Passive Smoking and Lung Cancer: Causal connection established 1986 i Reference: Wald et. al. BMJ 1986; 293: 1217-22.
  83. 83. Cumulative Meta-analysis of Spousal ETSExposure and Lung Cancer Risk 1981-1999
  84. 84. Secondhand Smoke ConclusionBased on the weight of evidence presented by: - the California EPA - the Surgeon General, and - strong recent evidence of an active smoking- breast cancer risk,The Expert Panel concluded that: The relationship between secondhand smoke and breast cancer in younger, primarily premenopausal women is consistent with causality.
  85. 85. Active Smoking ConclusionBased on the weight of evidence from: - epidemiologic studies, - toxicological studies and - understanding of biological mechanisms,The Expert Panel concluded that: The relationships between active smoking and both pre- and postmenopausal breast cancer are consistent with causality.
  86. 86. Lung disease in relation to tobacco exposure Ioana Munteanu , Fl. Mihaltan “Marius Nasta” Institute ofpneumology Bucharest Romania
  87. 87. • Effects of cigarette smoke on the lung• History• Lung diseases
  88. 88. • Effects of cigarette smoke on the lung• History• Lung disease
  89. 89. Europe - 650,000 deaths / year are attribute to smoking
  90. 90. THE MECHANISM OF INDUCED LUNG INJURY 850-900 Pathology of the Lung European Respiratory Society Monograph, Vol. 39, 2007E TOBACCO SMOKE dited by W. chemicals 4000 Timens and H.H. Popper 60 carcinogenic CILIARY CLEARANCE DISTURBANCE OXIDANTS, OXIDE, AROMATIC HYDROCARBONS, ALDEHYDES, NITROSAMINES ACIDS, AMMONIA RETENTION OF MUCUS AND TOXINS GROWTH SIGNALSLOCAL IRRITATION OF THE DESTRUCTION OF CHROMOSOMERESPIRATORY EPITHELIUM AND DNAINJURY / CELL DEATH EXPRESSION OF ONCOGENESINFLUX OF NEUTROPHILS INFECTION CARCINOGENESIS INFLAMMATIONCOPD AND OTHER LUNG CANCERINFLAMMATORY LUNG DISEASES
  91. 91. Pulmonary disease in relation to smoking• Diseases in which smoking is directly involved and has negative effects on their evolution – COPD – Lung cancer
  92. 92. Risk of developing a disease caused by smoking• As compared to nonsmokers, smoking is estimated to increase the risk of: – men developing lung cancer by 23 times, – women developing lung cancer by 13 times, and – dying of chronic obstructive lung diseases (such as chronic bronchitis and emphysema) by 12 to 13 times. http://www.cdc.gov/tobacco/data_statistics/fact_sheets/he alth_effects/effects_cig_smoking/
  93. 93. Pulmonary disease in relation to smoking• Diseases whose evolution is worsened by smoking• Chronic inflammatory diseases Asthma Emphysema due to α1-antitrypsin deficiency Chronic bronchitis• Neoplasms Cavum tumors Tumors of the mouth Laryngeal tumors• Infectious Diseases Rhinitis, pharyngitis, pneumonia, influenza, tuberculosis• Interstitial lung Disease Pneumoconiosis, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, bronchiolitis
  94. 94. • Effects of cigarette smoke on the lung• History• Lung disease
  95. 95. History In 1950 , Prof . R. Doll began his studies on the role of smoking as risk factor in lung cancer. He published in the British Medical Journal his conclusions; "The risk of developing the disease increases in proportion to the amount smoked. It may be 50 times as great among those who smoke 25 or more cigarettes a day as among non-smokers."In 1964 the Association of Surgeons ofthe U.S. presents the first cause and effectrelationship between smoking and lungcancer
  96. 96. 1981: Earliest evidence of the passive smoking involvement in lung cancerdevelopment Takeshi Hirayama (Japan) • 1992 Environmental Protection Agencys Respiratory Health Effects of Passive Smoking: Lung Cancer and Other Disorders complete their research on ETS • ETS was included in class A carcinogens, in the same category as asbestos, benzene and radon. • More than 3,000 lung cancer deaths per year were attributed to ETS. • The U.S. Surgeon General : The lung cancer risk for a nonsmoker whose spouse is a smoker is 20-30% higher.
  97. 97. • Effects of cigarette smoke on the lung• History• Lung diseases
  98. 98. • COPD
  99. 99. PATHOGENESIS AND PATHOPHYSIOLOGY OF LUNG LESIONS INDUCED BY TOBACCOCigarette smoke Oxidants Inflammation in the airways and lung Bronchial biopsies showed : Chronic inflammatory changes with increased no. of specific inflammatory cells Structural remodeling due to repeated injury and repair mechanisms Int. J. Environ Res. Public Health 2009
  100. 100. Lifetime risk of developing chronic obstructive pulmonary disease Dr Andrea S Gershon 2010• Prospective study : All individuals free of COPD in 1996 were monitored for up to 14 years• The cumulative incidence of physician-diagnosed COPD over a lifetime adjusted for the competing risk of death was calculated• Results were stratified by sex, socioeconomic status and a rural or urban setting.• Findings A total of 579 466 individuals were diagnosed with COPD by a physician over the study period. – The overall lifetime risk of physician-diagnosed COPD at age 80 years was 27,6%. – Lifetime risk was higher in men than in women (29,7% vs 25,6%), – Individuals of lower socioeconomic status had an increased risk as compared to those of higher socioeconomic status (32,1% vs 23,0%), – The risk was higher in individuals who lived in a rural setting than in those who lived in an urban setting (32,4% vs 26,7%).• Interpretation• About one in four individuals are likely to be diagnosed and receive medical attention for COPD during their lifetime. Clinical evidence-based approaches, public health action, and more research are needed to identify effective strategies to prevent COPD and ensure that those with the disease have the highest quality of life possible
  101. 101. Smoking Cessation: Improvement in Postbronchodilator FEV1 Decline Susceptible smokers develop significant lung function decline Sustained Quitters 2.9 Continuous Smokers Postbronchodilator FEV1 L 2.8 2.7 2.6 2.5 The Lung Health Study (LHS) (N=5887) aged 35 to 60 years 2.4 5 years follow up Screen 2 1 2 3 4 5 Follow up (y)Anthonisen et al. JAMA. 1994;272(19):1497-1505; Kanner et al. Am J Med. 1999;106(4):410-416.
  102. 102. COPDThe exact role of smoking cessation on airway inflammation inpatients with COPD remains unknownStudies- Inflammation persists despite smoking cessationEXPLANATION •Persistence of an inflammatory trigger that maintains ongoing local inflammatory response •In COPD, persistent inflammation may be due to destruction of tissue in the airways induced by smokingNEW HYPOTHESES - COPD may have an autoimmune component,contributing to persistent inflammation even after smokingcessation Int. J. Environ Res. Public Health 2009
  103. 103. Predictors of Mortality in Patients with Stable COPD Esteban, 2008,Five-year prospective cohort study. 600 stable COPD patients recruited consecutively.Which clinical factors are associated with mortality in patients with stable COPD
  104. 104. • Asthma
  105. 105. Asthma smoking is a risk candidate for development of asthma smoking is more prevalent in individuals with asthma than in those without smoking is associated with decreased asthma control and increased risk of mortality and asthma attacks and exacerbations smokers with and without asthma may have different risk factors for smoking onset as well as different smoking motives and outcome expectanciessmoking cessation is associated with improvements in lung functioning and asthma symptoms. Eur Respir J 2004; 24: 822–833
  106. 106. Effects of smoking cessation on airflow obstruction and quality of life in asthmatic smokers. Jang AS,Korea 2010 22 continue to smoke 32 subjects 10 quit smoking
  107. 107. Lung cancer
  108. 108. The lung cancer risks of smoking vary with the quantitative aspects of smoking• Duration of smoking is the stronger determinant of lung cancer risk in some analyses ( Doll and Peto)• Starting age is linked to duration of smoking• Depth of inhalation• Number of cigarettes smoked• Years as nonsmoker• The cigarette type
  109. 109. THE LUNG CANCER RISK INCREASEs EXPONENTIALLY WITH THE NUMBER OF YEARS AND THE NUMBER OF CIGARETTE SMOKED BY DAY Lubin J H , Caporaso N E Cancer Epidemiol Biomarkers Prev 2006;15:517-523
  110. 110. Lung Cancer in Patients with Chronic Obstructive Pulmonary Disease Incidence and Predicting Factors Juan P. de Torres, Am. J. Respir. Crit. Care Med. October 15, 2011• A cohort of 2,507 patients without initial clinical or radiologic evidence of lung cancer was monitored over a period of 60 months on average (30–90) .• 215 patients with COPD developed lung cancer (incidence density of 16.7 cases per 1,000 person- years)• Squamous cell carcinoma is the most frequent histologic type.• Older patients with milder airflow obstruction (GOLD I and II) and lower body mass index.• Lung cancer incidence was lower in patients with worse severity of airflow obstruction.
  111. 111. Tobacco-attributable cancer burden in the UK in 2010, DM Parkin
  112. 112. Pack-Years of Cigarette Smoking as a Prognostic Factorin Patients With Stage IIIB/IV Nonsmall Cell Lung CancerJanjigian, Cancer 2010 2010 patients with stage IIIB/IV NSCLC between June 2003 and March 2006.
  113. 113. Infectious diseases - tuberculosis
  114. 114. The association between smoking and tuberculosis has been investigated since 1918 Int J Tuberc Lung Dis. 2007 Mar;11(3):258-62. Associations between tobacco and tuberculosis
  115. 115. The reduction of tuberculosis risks by smoking cessation Wen, et al.--2010
  116. 116. Smoking and mortality from tuberculosis andother diseases in India: retrospective study of43 000 adult male deaths and 35 000 controls Gajalakshmi, et al.--2009
  117. 117. Tobacco smoking and pulmonary tuberculosis Kolappan, Gopi--2002
  118. 118. Thank you
  119. 119. Genetic and Lifestyle Modifiers of Cancer Smoking on Disease Risk Woon-Puay Koh Saw Swee Hock School of Public Health National University of Singapore
  120. 120. List of cancers associated with cigarette smoking……… Lung Mouth and pharynx Larynx Esophagus Stomach Pancreas Liver Cervix Bladder Kidney Colorectum Breast
  121. 121. Do all smokers get cancer?
  122. 122. What modifies a smoker’s risk of cancer? Risk of lung cancer in smokers  Body mass index Risk of colorectal cancer in smokers  Genetic polymorphism Findings from The Singapore Chinese Health Study
  123. 123. Singapore Chinese Health StudyEligibility criteria: Singapore Chinese, housing estate residents, ages 45-74 yearsRecruitment period: April 1993 to December 1998Cohort size: Total of 63,257, with 35,298 women and 27,959 menBaseline data: In-person interview, focus on current diet-using validated 165-item food frequency questionnaire, smoking, alcohol, physical activity, occupational exposures, detailed menstrual and reproductive history from womenBiospecimen : Blood/buccal cells and spot urine from consenting subjects between 1999 and 2004. A total of 32,575 subjects contributed biospecimens, representing 51% of the cohort.Follow-up: Disease registry, death registry, address/phone updates via linkage and 2 follow-up interviews
  124. 124. Cigarette smoking 31% ever smokers among the 61,321 subjects Men (n=27,292) Women (n=34,028) Never Former Current Never Former CurrentPercent 42.2% 21.4% 36.4% 91.3% 2.5% 6.2% Heavy smokers (12%):  Started to smoke before 15 years of age AND smoked at least 13 cigarettes per day Light smokers (88%):  Started to smoke after 15 years of age OR smoked 12 or less cigarettes per day Compared to never smokers, heavy smokers were older, less educated, more likely to be male, had lower body mass index (leaner), and drank more alcohol
  125. 125. Cigarettes and Lung Cancer Risk 1,042 incident lung cancer cases in this cohort after a mean follow-up of 10.7 yearsSmoking Lung cancer Lung cancerstatus RR (95% CI)* # sticks/day RR (95% CI)*Never 1.00 Never 1.00 2.24 (1.81-2.78) 1-12 4.32 (3.55-5.23)Former 13-22 6.61 (5.46-8.02)Current 5.85 (4.99-6.87) 23+ 9.49 (7.58-11.88) P for trend <0.0001 *Hazard ratios (HRs) were adjusted for age at baseline, sex, dialect group and year of interview; CI, confidence interval. Koh et al Br J Cancer (2010);102:610-4.
  126. 126. Body Mass Index in Relation to Lung Cancer Risk by Smoking Status Never Former CurrentBody Mass smokers smokers smokersIndex (kg/m2) Adj. HR Adj. HR Adj. HR (95% CI)* (95% CI)* (95% CI)* <20 1.00 1.00 1.00 20-<24 1.02 (0.71-1.46) 0.92 (0.57-1.48) 0.81 (0.67-0.99) 24-<28 0.72 (0.46-1.10) 1.01 (0.59-1.74) 0.62 (0.46-0.82) 28+ 0.81 (0.46-1.44) 0.97 (0.44-2.12) 0.50 (0.28-0.88)P for trend 0.08 0.89 0.0001 Koh et al Br J Cancer (2010);102:610-4.
  127. 127. Smoking and lung cancer risk by levels of BMI <20 kg/m2 20-<24 kg/m2 24-<28 kg/m2 >=28 kg/m2Smokingstatus HR (95% CI)* HR (95% CI)* HR (95% CI)* HR (95% CI)*Never 1.00 1.00 1.00 1.00Former 2.46 1.97 2.96 1.99 (1.40-4.32) (1.48-2.62) (1.84-4.76) (0.88-4.52)Current 7.21 5.20 5.50 3.21 (4.84-10.75) (4.22-6.41) (3.64-8.32) (1.58-6.51) Koh et al Br J Cancer (2010);102:610-4.
  128. 128. Smoking and lung cancer risk by levels of BMI <20 kg/m2 20-<24 kg/m2 24-<28 kg/m2 >=28 kg/m2 HR (95% CI)* HR (95% CI)* HR (95% CI)* HR (95% CI)*Cigarettes per day (risk relative to never smokers)1-12 6.18 3.65 3.65 2.90 (3.98-9.58) (2.82-4.73) (2.12-6.28) (1.15-7.27)13-22 7.92 6.39 5.41 2.21 (5.01-12.53) (4.98-8.20) (3.23-9.05) (0.71-6.86)23+ 11.12 8.53 9.01 6.37 (6.60-18.70) (6.35-11.50) (5.04-16.10) (2.10-19.30)P trend <0.0001 <0.0001 <0.0001 0.0001 Koh et al Br J Cancer (2010);102:610-4.
  129. 129. Biological plausibility Body mass index influences a smoker’s risk of lung cancer Lean smokers have increased oxidative DNA damage relative to obese smokers Lean smokers have increased susceptibility to tobacco carcinogens-induced DNA damage
  130. 130. Public Health Implication Rapid increase in smoking prevalence in developing countries such as China and India in which people still have relatively low body weights The adverse effect of smoking would be stronger in the developing countries than the developed world
  131. 131. Smoking and Colorectal Cancer Risk
  132. 132. “Lifestyle” cancer  Obesity  Western diet  Physical inactivity  Smoking
  133. 133. Current smoking and colorectal cancerrisk: Meta-analysis (18 cohort studies) Tsoi KK et al Clin Gastroenterol Hepatol. 2009;7:682-688
  134. 134. Colonic carcinogens in cigarette Polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HAAs) Metabolic activation to form highly reactive mutagens that readily react with DNA bases Undergo detoxification through conjugation reactions with the phase II enzymes to be excreted
  135. 135. GST enzymes 5 main classes: alpha (GSTA), mu (GSTM), pi (GSTP), theta (GSTT) and zeta (GSTZ) GSTM1, GSTT1 and GSTP1 are detoxification enzymes that have been known to metabolize a wide range of carcinogens from tobacco smoke and diet, including HAAs and PAHs High expression in the intestinal tract. These GSTs are polymorphic enzymes with inter-individual variations in enzymatic level and activity.
  136. 136. GSTM1 and GSTT1 polymorphisms The homozygous deletion genotypes of GSTM1 and GSTT1 result in an absence of GSTM1 and GSTT1 expression
  137. 137. GSTP1 polymorphism A transition of adenine (A) to guanine (G) at nucleotide 313 in exon 5 of the GSTP1 gene results in a change from isoleucine (Ile) to valine (Val) at position 104 in the amino acid sequence of the corresponding protein. GSTP1 BB and the heterozygous variant, GSTP1 AB, have been shown to possess decreased specific activity and affinity for substrates
  138. 138. GST/Smoking/Colorectal Cancer GSTs can deactivate HAAs and PAHs Hence, individuals with genetically determined decreaseinin GST HAAs and PAHs cigarette smokeenzyme activity may have increased risk of colorectal cancer risk associated with smoking Smokers Increased risk of Colorectal Cancer
  139. 139. Nested case-control study within the Singapore Chinese Health Study 480 incident colorectal cancer cases within the cohort diagnosed as of April 30, 2005 identified by linkage with nationwide cancer registry and confirmed by verification of histological reports or medical notes. 1167 controls from a random 3% of the cohort population and who consented to give us blood
  140. 140. Cigarettes and Colorectal Cancer Colorectal Colon RectalSmoking level OR (95% CI)* OR (95% CI)* OR (95% CI)*Never 1.00 1.00 1.00Light smoker 1.16 (0.87-1.54) 0.94 (0.66-1.34) 1.45 (0.99-2.13)Heavy smoker 2.95 (1.72-5.06) 2.18 (1.11-4.29) 4.12 (2.15-7.88)P for trend 0.002 0.246 <0.0001 Intensity of smoking is associated with colorectal cancer risk Koh et al, Carcinogenesis. 2011; 32:1507-11
  141. 141. GSTs and Colorectal Cancer Colorectal Colon RectalGSTM1 OR (95% CI)* OR (95% CI)* OR (95% CI)*Present 1.00 1.00 1.00Null 0.92 (0.73-1.16) 0.83 (0.62-1.10) 1.06 (0.77-1.46) Colorectal Colon RectalGSTT1 No clear association between CI)* OR (95% CI)* OR (95% CI)* OR (95% polymorphisms of GSTM1, GSTT1 orPresent 1.00 1.00 1.00Null 1.12 (0.89-1.41) 1.23 (0.93-1.61) 1.03 (0.75-1.41) GSTP1 and colorectal cancer risk Colorectal Colon RectalGSTP1 OR (95% CI)* OR (95% CI)* OR (95% CI)*AA 1.00 1.00 1.00AB 0.82 (0.63-1.06) 0.86 (0.63-1.18) 0.76 (0.53-1.09)BB 0.65 (0.35-1.21) 0.74 (0.35-1.58) 0.55 (0.22-1.37)AB/BB 0.80 (0.62-1.02) 0.85 (0.63-1.14) 0.73 (0.52-1.04)
  142. 142. GSTs and Colorectal Cancer No. of “null Colorectal Colon Rectal or low OR (95% CI)* OR (95% CI)* OR (95% CI)* activity” GST genotypes 0No clear 1.00 association between number of 1.00 1.00 1genetic polymorphisms of GST 1.06 (0.70-1.61) 1.02 (0.76-1.36) 0.98 (0.68-1.40) enzymes 2 0.95 (0.69-1.31) 0.89 (0.60-1.31) 1.06 (0.68-1.65) 3 and colorectal cancer risk (0.19-1.23) 0.76 (0.44-1.32) 0.95 (0.50-1.78) 0.48 P for trend 0.410 0.601 0.498Null or low activity genotypes: GSTM1 Null, GSTT1 Null, GSTP1 AB/BB Koh et al, Carcinogenesis. 2011; 32:1507-11
  143. 143. GSTs, Cigarettes and Colorectal CancerWith zero GST “null or low activity” genotype (22.5%) Colorectal Colon RectalSmoking level OR (95% CI)* OR (95% CI)* OR (95% CI)*Never 1.00 1.00 1.00Light smoker 0.82 (0.43-1.55) 0.35 (0.15-0.84) 2.00 (0.81-4.90)Heavy smoker 1.34 (0.38-4.76) 0.68 (0.14-3.22) 3.23 (0.57-18.1)P for trend 0.916 0.087 0.085Null or low activity genotypes: GSTM1 Null, GSTT1 Null, GSTP1 AB/BB Koh et al, Carcinogenesis. 2011; 32:1507-11
  144. 144. GSTs, Cigarettes and Colorectal Cancer With one GST “null or low activity” genotype (41.4%) Colorectal Colon RectalSmoking level OR (95% CI)* OR (95% CI)* OR (95% CI)*Never 1.00 1.00 1.00Light smoker 1.09 (0.70-1.68) 0.86 (0.50-1.49) 1.37 (0.77-2.44)Heavy smoker 2.43 (1.01-5.86) 2.05 (0.66-6.33) 3.01 (1.05-8.62)P for trend 0.143 0.732 0.052Null or low activity genotypes: GSTM1 Null, GSTT1 Null, GSTP1 AB/BB Koh et al, Carcinogenesis. 2011; 32:1507-11
  145. 145. GSTs, Cigarettes and Colorectal CancerWith two or three GST “null or low activity” genotypes (36.1%) Colorectal Colon Rectal Smoking level OR (95% CI)* OR (95% CI)* OR (95% CI)* Never 1.00 1.00 1.00 Light smoker 1.69 (1.03-2.77) 1.92 (1.04-3.54) 1.39 (0.71-2.72) Heavy smoker 5.43 (2.22-13.2) 4.25 (1.36-13.3) 6.04 (2.14-17.0) P for trend 0.0002 0.005 0.003 Null or low activity genotypes: GSTM1 Null, GSTT1 Null, GSTP1 AB/BB
  146. 146. Biological Plausibility The GSTM1/GSTT1/GSTP1 genotypic profile of a cigarette smoker affects his/her risk of developing colorectal cancer due to exposure from colorectal procarcinogens present in tobacco smoke. GST enzymes play important role in the detoxification of colorectal carcinogens in tobacco smoke.
  147. 147. Gene-Environment-Smoking Interaction Wide variation in cancer incidence among smokers A range of genetic and lifestyle factors act as determinants of a smoker’s risk to cancer by influencing the uptake and metabolism of tobacco carcinogens, inflammatory response to the tobacco- induced lung damage and DNA repair
  148. 148. Gene-Environment-Smoking Interaction Understand the mechanistic pathway of tobacco-linked carcinogenesis Identify important pathways of activation and/or deactivation of tobacco-related carcinogens Explain heterogeneity in risk of smoking- related cancer Identify smokers at higher risk of cancer risk Provide strong motivation to quit smoking
  149. 149. Acknowledgement  Cohort Study Team  Professor Mimi Yu  Singapore Cancer Registry  Assoc Prof Yuan Jian-Min  Dr Renwei Wang  Professor Lee Hin PengSupported by Grants from the National Cancer Institute (NIH)

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